This program evaluates the application of precision acoustic fields to penetrating neural implants to prevent electrode impedance rise and improve implant longevity. Problem to be solved: Chronic neural implants hold great potential for illuminating features of neural function and treating neurological disorders. Penetrating electrode arrays provide direct access to neural signals across the central and peripheral nervous system with high spatial resolution. A consistent point of failure for chronically implanted microelectrode arrays is the poor longevity and functionality of these devices, an issue that must be addressed to facilitate clinical translation of neural implant technology. One major failure mode of electrode arrays is the host tissue?s immune response (i.e., foreign body response or FBR), which causes glial scarring and neural cell loss near electrode sites, impairing recording quality. Efforts have been made to minimize the brain FBR through electrode design and pharmacological treatment, but there is no optimal solution; performance variability persists for all array types. We propose an innovative means of reducing the FBR by using low-intensity pulsed ultrasound to acoustically promote localized neurotrophic release in cortical tissue surrounding a neural implant. Studies will also focus on implanted transducers and provide new insights into the possible neuroprotective effects of frequencies above conventional transcranial ultrasound studies. Hypothesis. Application of localized ultrasonic fields of different acoustic parameters and treatment intervals can affect release of neurotrophic factors, and can be used to mitigate glial scarring, promote neural implant longevity, and neuron health. Aim 1 ? Design and characterize head-mounted ultrasound transducer for chronic in vivo studies. Acceptance Criteria: Acoustic stimulation is well-coupled and is thermally safe (<1C temperature increase in tissue model). Aim 2 ? Identify ultrasonic parameters that safely stimulate acute neurotrophin release in cortical tissue below neural activation thresholds, in an in vivo model. Acceptance Criteria: Significantly increase neurotrophin release (e.g., BDNF) with low-intensity ultrasound stimulation, as measured through cerebral fluid sampling via an implanted microdialysis probe and tissue histology, without damaging neural tissue. Aim 3 ? Evaluate effects of low-intensity ultrasound stimulation on long-term neural electrode performance and glial scarring in cortical tissue in an in vivo model. Acceptance Criteria: Significantly (?=0.05) reduce the change in electrode impedance as compared to experimental control (no acoustic stimulation); significantly (?=0.05) improve neural recording quality (number of neural units, signal-to- noise ratios), over a 4-week period. Aim 4 ? Evaluate the effects of low-intensity ultrasound stimulation on the microglia response to a neural implant in an in vivo model. Acceptance Criteria: Significant reduction in microglia activation and migration within 200 m of the electrode-tissue interface with periodic low-intensity ultrasound stimulation over a 4-week period.